The general purpose of this proposal is to assess the contributions of smooth muscle cell (SMC) large conductance Ca2+-activated potassium (BKCa) channels to coronary vascular dysfunction in heart failure with preserved ejection fraction (HFpEF) and examine the effects of exercise training on this process. Our long-term objective is to identify the molecular mechanisms underlying coronary vascular dysfunction in HFpEF determine the efficacy of exercise as a viable treatment for preserving normal coronary vascular function (CVF). The specific aims of this proposal are: 1.) To determine if the loss of SMC BKCa channel expression/activity in miniature swine with HFpEF is a key mechanism underlying coronary vascular dysfunction, examine the role of this SMC channel in the disease progression of HFpEF, and identify molecular signaling mechanisms regulating these processes; and 2.) To determine if exercise training increases SMC BKCa channel activity/expression thus preventing coronary vascular dysfunction and deterioration of LV functional and metabolic relationships in miniature swine with HFpEF. To examine these issues, we will use a novel miniature swine model of HFpEF, which is considered both clinically relevant and a gold standard for translational impact regarding CVF in humans. Temporal studies will be used to test whether SMC BKCa channels precede the development of HFpEF or are a manifestation of the disease process. Further, we will perform experiments following 15 weeks of exercise to test the hypothesis that chronic exercise preserves BKCa channel activity/expression, coronary vascular function, and LV functional and metabolic relationships in HFpEF utilizing training protocols of differing intensity. Comprehensive in vivo (Ultrasound; Coronary Blood Flow; LV function, i.e. Pressure-Volume loops; metabolic, i.e. Myocardial VO2) and in vitro (isolated arteriole, patch-clamp) experiments will be performed in the presence of BKCa channel agonists (NS-1619, HENA) and antagonists (Penitrem A). Using an integrated approach, these techniques will allow us to determine if the mechanism underlying impaired CVF in HF is the loss of SMC BKCa channel expression/activity, examine the role of this SMC channel in disease progression, and determine the effectiveness of exercise as a treatment for preserving normal coronary vascular and LV function in miniature swine with HFpEF.